Cyclopentane heptan (ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents

ABSTRACT

The present invention provides cyclopentane heptanoic acid, 2 heteroaryl alkyl or alkenyl derivatives which may be substituted in the 1-position with hydroxyl, alkyloxy, amino and amido groups, e.g. 1-OH cyclopentane heptanoic acid, 2 heteroarylalkenyl derivatives. In particular, these derivatives are 7-[5-hydroxy-2-(heteroatom-substituted hydroxyhydrocarbyl)-3-hydroxycyclopentyl]heptanoic or heptenoic acids and amine, amide, ether, ester and alchohol derivatives of said acids wherein one or more of said hydroxy groups are replaced with an ether group. These compounds are potent ocular hypotensive and are particularly suited for the management of glaucoma. Moreover, the compounds of this invention are smooth muscle relaxants with broad application in systemic hypertensive and pulmonary diseases; with additional application in gastrointestinal disease, reproduction, fertility, incontinence, shock, inflammation, immune regulation, disorder of bone metabolism, renal dysfunction, cancer and other hypoproliferative diseases.

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of Ser. No. 09/491,180 filed Jan. 25,2000, which is a continuation of Ser. No. 08/994,810 filed Dec. 19, 1997now U.S. Pat. No. 6,096,902, which is a continuation of Ser. No.08/608,794 filed Feb. 29, 1996, now U.S. Pat. No. 5,741,810.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention provides cyclopentane heptanoic acid, 2 heteroarylalkyl or alkenyl derivatives which may be substituted in the 1-positionwith hydroxyl, alkyloxy, amino and amido groups, e.g. 1-OH cyclopentaneheptanoic acid, 2 heteroarylalkenyl derivatives. In particular, thesederivatives are 7-[5-hydroxy-2-(heteroatom-substitutedhydroxyhydrocarbyl)-3-hydroxycyclopentyl]heptanoic or heptenoic acidsand amine, amide, ether, ester and alcohol derivatives of said acidswherein one or more of said hydroxy groups are replaced with an ethergroup. These compounds are potent ocular hypotensives and areparticularly suited for the management of glaucoma. Moreover, thecompounds of this invention are smooth muscle relaxants with broadapplication in systemic hypertensive and pulmonary diseases; withadditional application in gastrointestinal disease, reproduction,fertility, incontinence, shock, inflammation, immune regulation,disorder of bone metabolism, renal dysfunction, cancer and otherhyperproliferative diseases.

2. Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure angle-closure glaucoma, theanterior chamber is shallow, the filtration angle is narrowed, and theiris may obstruct the trabecular meshwork at the entrance of the canalof Schlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [[e.g. prostaglandin F_(2α)(PGF_(2α))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The U.S. Ser. No. 596,430 (filed Oct. 10, 1990), relates tocertain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl,11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF_(2α). Intraocularpressure reducing 15-acyl prostaglandins are disclosed in theapplication U.S. Ser. No. 175,476 (filed Dec. 29, 1993). Similarly,11,15- 9,15 and 9,11-diesters of prostaglandins, for example11,15-dipivaloyl PGF_(2α) are known to have ocular hypotensive activity.See the patent applications U.S. Ser. No. 385,645 (filed Jul. 7, 1989,now U.S. Pat. No. 4,994,274), Ser. No. 584,370 (filed Sep. 18, 1990, nowU.S. Pat. No. 5,028,624) and Ser. No. 585,284 (Sep. 18, 1990, now U.S.Pat. No. 5,034,413).

Other patents and patent applications assigned to Allergan, Inc.disclose and claim other compounds which are useful in treatingincreased intraocular pressure and thus are useful in the treatment ofglaucoma. Said patents and patent applications include U.S. patentapplication Ser. No. 08/174,535, which is entitled Cyclopentane (ene)Heptenoic or Heptanoic Acids and Derivatives Thereof Useful asTherapeutic Agents and was filed on Dec. 28, 1993 and U.S. patentapplication Ser. No. 08/443,992, which is entitled CyclopentaneHeptan(ene)oic Acid, 2-Heteroarylalkenyl Derivatives as TherapeuticAgents and was filed on May 18, 1995.

The disclosures of all of these patent applications are hereby expresslyincorporated by reference.

SUMMARY OF THE INVENTION

The present invention concerns a method of treating ocular hypertensionwhich comprises administering to a mammal having ocular hypertension atherapeutically effective amount of a compound of formula I

wherein the wavy segments represent an α or β bond, dashed linesrepresent a double bond or a single bond, R is a heteroaryl radical or asubstituted heteroaryl radical, R¹ is hydroxyl or a hydrocarbyloxy orheteroatom sustituted hydrocarbyloxy comprising up to 20, e.g. up to 10carbon atoms, and preferably a lower alkyloxy radical having up to sixcarbon atoms, X is selected from the group consisting of —OR⁶ and—N(R⁶)₂, wherein R⁶ is hydrogen or a lower alkyl radical having from 1to 6 carbon atoms and Y is ═O or represents 2 hydrogen radicals andfurther provided that at least one of R¹ is a hydrocarbyloxy orheteroatom substituted hydrocarbyloxy.

In particular, the substituents on the heteroaryl radical may beselected from the group consisting of lower alkyl, e.g. C₁ to C₆ alkyl;halogen, e.g. fluoro, chloro, iodo and bromo; trifluoromethyl (CF₃);COR⁷, e.g. COCH₃; COCF₃; SO₂NR⁷, SO₂NH₂; NO₂; CN; etc., wherein R⁷ is alower alkyl radical having from 1 to 6 carbon atoms.

In a further aspect, the present invention relates to an ophthalmicsolution comprising a therapeutically effective amount of a compound offormula (I), wherein the symbols have the above meanings, or apharmaceutically acceptable salt thereof, in admixture with a non-toxic,ophthalmically acceptable liquid vehicle, packaged in a containersuitable for metered application.

In a still further aspect, the present invention relates to apharmaceutical product, comprising

a container adapted to dispense its contents in a metered form; and

an ophthalmic solution therein, as hereinabove defined.

A further aspect of the present invention provides methods of treatingcardiovascular, pulmonary-respiratory, gastrointestinal, productive,allergic disease, shock and ocular hypertension which comprisesadministering an effective amount of a compound represented by theformula I.

Finally, certain of the compounds represented by the above formula,disclosed below and utilized in the methods of the present invention arenovel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a schematic of the chemical synthesis of certain 1-carboxylicacid compounds and ester derivatives thereof specifically disclosed asExample 4(a)-(e) and 5(a)-(e) below.

FIG. 2 is a schematic of the chemical synthesis of certain 1-amidocompounds specifically disclosed as Examples 6(b)-(g) below.

FIG. 3 is a schematic of the chemical synthesis of certain 1-isopropylester compounds specifically disclosed as Examples 7(f)-(i), below.

FIG. 4 is a schematic of the chemical synthesis of certain15-methoxy-substituted carboxylic acid compounds and isopropylderivatives thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of cyclopentane heptan(ene)oicacid, 2-heteroaryl alkyl or alkenyl derivatives as therapeutic agents,e.g. as ocular hypotensives. The compounds used in accordance with thepresent invention are encompassed by the following structural formula I:

wherein the substituents and symbols are as hereinabove defined.

Preferably, the compounds used in accordance with the present inventionhave the following structural formula II:

wherein the hatched segments represent α bonds, the solid trianglerepresents a γ bond and the substituents and symbols are as hereinabovedefined. The dotted lines on bonds between carbons 5 and 6 (C-5) andcarbons 13 and 14 (C-13) indicate a single or double bond. If two solidlines are used at C-5, or C-13, it indicates a specific configurationfor that double bond. Hatched lines used at position C-8, C-9 and C-11indicate the α configuration. A triangle at position C-12 represents βorientation. A more preferred group of the compounds of the presentinvention includes compounds that have the following structural formulaIII:

wherein Z is selected from the group consisting of O and S, A isselected from the group consisting of N, —CH, and C, R² is selected fromthe group consisting of hydrogen, halogen, and lower alkyl having from 1to 6 carbon atoms, R³ and R⁴ are selected from the group consisting ofhydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, or,together with

R³ and R⁴ forms a condensed aryl ring and R⁵ is a lower alkyl havingfrom 1 to 6 carbon atoms. Preferably, when X is —N(R⁶)₂, Y is ═O.

More preferably, R⁵ is methyl and at least one of R², R³ or R⁴ areindependently selected from the group consisting of chloro, bromo andlower alkyl. In one aspect of the invention, at least one of R², R³ orR⁴ is chloro or bromo, and more preferably at least one of R², R³ or R⁴is bromo or at least two of R², R³ or R⁴ are chloro or bromo. In anotheraspect of this invention, at least one of R², R³ or R⁴ is ethyl, propyl,or butyl.

Another preferred group includes compounds having the formula IV:

The above compounds of the present invention may be prepared by methodsthat are known in the art or according to the working examples below.The compounds, below, are especially preferred representative of thecompounds of the present invention.

7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(3-(2-methyl)-thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

Isopropyl7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate.

A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Of particular interest are saltsformed with inorganic ions, such as sodium, potassium, calcium,magnesium and zinc.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate the application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

The invention is further illustrated by the following non-limitingExamples, which are summarized in the reaction schemes of FIGS. 1through 4, wherein the compounds are identified by the same designatorin both the Examples and the Figures.

COMPOUND 5a7-[3α,5α,-Dihydroxy-2-(3α-hydroxy-5-(2-(3-chloro)benzothienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

Step 1: Preparation of Enone 2a

To a suspension of sodium hydride (27 mg, 1.15 mmol) in tetrahydrofuran(THF) (2.0 mL) cooled to 0° C. was added dimethyl 4-(2-(3-chloro)benzothienyl)-2-oxo-butylphosphonate(363 mg, 1.15 mmol) in THF (2.2 mL).(In this Example, benzothienyl is an example of the hetero aryl radicalsrepresented by R in the disclosure and claims and Ar in the Figures.)After 0.25 h a solution of the aldehyde 1 (507 mg, 1.04 mmol) in THF(2.0 mL) was added and the reaction was allowed to slowly warm to 23° C.over a period of 8 h. (In FIG. 1 THP represents tetrahydropyranyl.) Thereaction solution was quenched with saturated aqueous NH₄Cl andextracted with ethyl acetate (EtOAc.) The aqueous phase was madeslightly acidic and extracted again with EtOAc. The combined organicswere washed with brine, dried over MgSO₄, filtered and concentrated invacuo. Flash column chromatography (silica gel, 2:1 hexane/EtOAc) gave729 mg of enone 2a.

Step 2: Preparation of Alcohol 3a

Sodium tetrahydridoborate (40 mg, 1.05 mmol) was added to a solution ofthe enone (729 mg, 1.05 mmol) in methanol (MeOH)(2.1 mL) at 0° C. After2 h the solvent was removed in vacuo and the residue was stirred with 1NNaOH and EtOAc for 0.5 h. The organic portion was separated, dried overMgSO₄, filtered and concentrated in vacuo. The α-alcohol 3a wasseparated by flash column chromatography or HPLC (silica gel, 3:1hexane/EtOAc).

Step 3: Preparation of Triol 4a:

A solution of the alcohol 3a and pyridinium p-toluene sulfonate (PPTs)(53 mg, 0.212 mmol) in MeOH(0.4mL) was heated at 40° C. for 4 h. Thesolvent was removed in vacuo and the residue was diluted with EtOAc andthen washed with 1N HCl, saturated aqueous NaHCO₃ and brine. The organicportion was dried over MgSO₄, filtered and concentrated in vacuo thetriol 4a.

Step 4: Preparation of Carboxlic Acid 5a

The triol 4a was diluted with THF (0.8 mL) and lithium hydroxide (0.4 mLof a 0.5 N solution in H₂0, 0.186 mmol) was added. After 16 h thereaction was acidified with 1N HCl and extracted with EtOAc. The organicportion was washed with brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash column chromatography (silicagel, 9:1 EtOAc/MeOH) to give 14.0 mg of free acid 5a.

By methods described for compound 5a, steps 1 through 4, the followingcompounds were prepared as illustrated in Scheme 1:

COMPOUND 5b7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicAcid

Prepared according to the procedures described above for 5a except theuse of dimethyl 4-(5-(2,3-dibromo)thienyl)-2-oxo-butylphosphonateafforded 45 mg of free acid 5b.

COMPOUND 5c7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-methyl)furanyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicAcid

Prepared according to the procedures described above for 5a except theuse of dimethyl 4-(5-(2-methyl)furanyl)-2-oxo-butylphosphonate afforded63.6 mg of free acid 5c.

COMPOUND 5d7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicAcid

Prepared according to the procedures described above for 5a except theuse of dimethyl 4-(3-(2,5-dibromo)thienyl)-2-oxo-butylphosphonateafforded 74 mg of free acid 5d.

COMPOUND 5e7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-bromo-3-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicAcid

Prepared according to the procedures described above for 5a except theuse of dimethyl 4-(5-(2-bromo-3-methyl)thienyl)-2-oxobutylphos-phonateafforded 40.6 mg of free acid 5e

Synthesis of amides 6b-g (Scheme 2)

COMPOUND 6b7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide

The 3α-triol 4b (27mg, 0.048 mmol) isolated from step 3 during synthesisof 5b, was placed in a tube with ammonium chloride (76 mg, 1.42 mmol).Ammonia gas ˜4.5 mL was condensed into the tube at −70° C. The tube wassealed and heated to 65° C. for 16 h. The tube was cooled to −70° C.,vented and the ammonia allowed to evaporate on its own accord. Theresidue was dissolved in 1:1 EtOAc/H₂O. The organic portion wasseparated, dried over MgSO₄, filtered and concentrated in vacuo. Flashcolumn chromatography (silica gel, 9:1 CH₂Cl₂/MeOH) gave 16.8 mg of thetitle compound 6b.

COMPOUND 6c7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-methyl)furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide

According to the procedures described above for preparation of 6b the3α-triol 4c (51 mg, 0.126 mmol) was converted to 25.1 mg of the titlecompound 6c.

COMPOUND 6d7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide

According to the procedures described above for the preparation of 6bthe 3α-triol 4d (24 mg, 0.42 mmol) was coverted to 12 mg of the titlecompound 6d.

COMPOUND 6e7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-bromo-3-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide

According to the procedures described above for the preparation of 6bthe 3α-triol 4e (63 mg, 0.126 mmol) was converted to 33 mg of the titlecompound 6e.

COMPOUND 6f7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide

According to the procedures described above for the preparation of 6bMethyl7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate4f (50 mg, 0.127 mmol) was coverted to 12 mg of the title compound 6f.

COMPOUND 6g7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide

According to the procedures described above for preparation of 6b Methyl7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate4 g (65 mg, 0.154 mmol) was converted to 35.8 mg of the tilte compound6g.

The isopropyl esters 7f-i were prepared as illustrated in Scheme 3 fromthe corresponding carboxylic acids 5f-i, which were prepared in ananalogous manner to carboxylic acids 5a-e:

COMPOUND 7f Isopropyl7-[3α,5α-bihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate

A solution of the previously prepared carboxylic acid 5f (11.0 mg, 0.029mmol) and O-isopropyl-N, N′-diisopropylisourea (270 mg. 1.45 mmol) inbenzene (1.5 mL) was heated to 75° C. for 4 h. The reaction mixture wasconcentrated in vacuo and the residue was purified by flash columnchromatography (silica gel, 100% EtOAc) to afford 3.7 mg of the titlecompound 7f.

COMPOUND 7g Isopropyl7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoate

According to the procedures described above for the preparation of 7fthe previously prepared carboxylic acid 5g (10 mg, 0.025 mmol) wasconverted to 7.3 mg of the title compound 7g.

COMPOUND 7h Isopropyl7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-methyl)thienyl)-1E-pentenyl)-cyclopentyl]-5Z-heptenoate

According to the procedures described above for the preparation of 7fthe previously prepared carboxylic acid 5h (10 mg, 0.025 mmol) wasconverted to 7.8 mg of the title compound 7h.

COMPOUND 7i Isopropyl7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)-cyclopentyl]-5Z-heptenoate

According to the procedures described above for the preparation of 7fthe7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)-cyclopentyl]-5Z-heptenoicacid 5i (10 mg, 0.025 mmol) was converted to 7.0 mg of the titlecompound 7i.

COMPOUND 11f7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

Step 1: Methylation of C-15 Hydroxyl Group

Methyl triflate (MEOTF) (97 mL, 0.86 mmol) was added to a solution ofthe mixture of alcohols 8f (160 mg, 0.28 mmol) and2,6-di-t-butyl-pyridine (0.22 mL, 1.00 mmol) in CH₂Cl₂ (1.5 mL) at 0° C.The reaction was then allowed to warm to room tempeature and stirringwas continued for 16 h. After quenching with saturated aqueous NaHCO₃the reaction was extracted with EtOAc. The organic portion was washedwith 1N HCl, brine, dried over MgSO₄, filtered and concentrated invacuo. Flash column chromatography (silica gel, 4:1 hexane/EtOAc)provided 123 mg of the mixture of 15α, β-methyl ethers 9f.

Step 2: Removal of the Bis-Tetrahydropyranyl Protecting Groups

A solution of alcohols 9f (123 mg, 0.214 mmol) and pyridiniump-toluenesulfonate (40 mg, 0.16 mmol) in MeOH (3.0 mL) was heated at 40°C. for 4 h. The solvent was removed in vacuo. The residue was dilutedwith EtOAc and then washed with 1N HCl, saturated aqueous NaHCO₃ andbrine. The organic portion was dried over MgSO₄, filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 1:1 hexane/EtOAc followed by 100% EtOAc)gave 20.6 mg of 15α-methyl ether 10f.

Step 4: Preparation Carboxylic Acid 11f

The ester of 10f (10 mg, 0.025 mmol) was diluted with THF (0.4 mL) andlithium hydroxide (0.2 mL of a 0.5 N solution in H₂O, 0.05 mmol) wasadded. After 16 h the reaction was acidified with 1N HCl and extractedwith EtOAc. The organic portion was washed with brine, dried over MgSO₄,and concentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 9:1 MeOH/EtOAc) to furnish 5.0 mg of thecarboxylic acid 11f.

COMPOUND 11i7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicAcid

According to the procedures described above for the preparation of 11fthe mixture of alcohols 8i (295 mg, 0.50 mmol) were converted to 9.4 mgof title compound 11i.

COMPOUND 12f Isopropyl7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenote12f

A mixture of ester 10f (20 mg, 0.05 mmol) and potassium carbonate (20.4mg, 0.15 mmol) in anhydrous isopropanol (3.0 mL) was heated at 100° C.for 16 h. The reaction was concentrated in vacuo and the residue asstirred with 1:1 EtOAc/H₂O (˜20 mL) for 0.5 h. The organic portion wasseparated, dried over MgSO₄, filtered and concentrated in vacuo.Purification of the residue by flash column chromatography (silica gel,2:1 hexane/EtOAc) provided 20.2 mg of the title compound 12f.

Certain of the above compounds were tested for activity in the variousin vitro assays described below and the results are reported in Tables 1and 2, below.

TABLE 1 Dog Ec₅₀ (nM) DP/IC₂₅ FP/EP₄ Platelets IOP Hyp/ AGN-# FP EP₁ EP₃EP₂ EP₄ Ratio TP aggreg inhib (1 day) Miosis

568 21190 0.03

0.8 23 0.03 692

24 23 1.0 >10⁴ 0.1%/ −2.7 1.13/ pinpoint

0.25

1.4

2.2 165 0.01 NA

291 3760 0.08 0.1%/ −2.1 0.75/ pinpoint

0.44

50

TABLE 2 Ec₅₀ (nM) DP/IC₂₅ FP/EP₄ Platelets Dog IOP AGN-# FP EP₁ EP₃ EP₂EP₄ Ratio TP aggreg inhib (1 day) Hyp/Miosis

35 620 0.06 NA 0.1%/−4.4 0.01%/−3.2 1.0/pinpoint 1.5/pinpoint

33 1630 0.02 NA 0.1%/−3.6 0.6/pinpoint

4 57 0.07

5 100 0.05

Activity at different prostanoid receptors was measured in vitro inisolated smooth muscle preparations. FP-activity was measured ascontraction of the isolated feline iris sphincter. EP₄-activity wasmeasured as relaxation of smooth muscle of isolated rabbit jugular vein.TP-vasoconstrictor activity was measured as contraction of rings of theisolated rat thoracic aorta. Effects on platelets from healthy humandonors were measured by incubating platelet-rich plasma with thecompounds described herein. Inhibition of aggregation was determined bythe ability of the compounds described herein to inhibit plateletaggregation in platelet-rich plasma induced by 20 μM adenosinediphosphate (ADP).

Potential therapeutic applications of the compounds described above arein osteoporosis, constipation, renal disorders, sexual dysfunction,baldness, diabetes, cancer and in disorder of immune regulation.

Many examples also have pronounced activity at the FP receptor,provisionally termed FP_(VASC) associated with the vascular endotheliumin the rabbit jugular vein preparation. Since such agents would bevasodilators they have potential in hypertension and any disease wheretissue blood perfusion is compromised. Such indications include, but arenot limited to, systemic hypertension, angina, stroke, retinal vasculardiseases, claudication, Raynauds disease, diabetes, and pulmonaryhypertension.

The effects of certain of the compounds of the working examples onintraocular pressure are also provided in the following tables. Thecompounds were prepared at the said concentrations in a vehiclecomprising 0.1% polysorbate 80 and 10 mM tris (hydroxy methyl)aminomethane hydrochloride (TRIS) base. Dogs were treated byadministering 25 μl to the ocular surface, the contralateral eyereceived vehicle as a control. Intraocular pressure was measured byapplanation pneumatonometry. Dog intraocular pressure was measuredimmediately before drug administration and at 6 hours thereafter.

The compounds of the invention may also be useful in the treatment ofvarious pathophysiological diseases including acute myocardialinfarction, vascular thrombosis, hypertension, pulmonary hypertension,ischemic heart disease, congestive heat failure, and angina pectoris, inwhich case the compounds may be administered by any means that effectvasodilation and thereby relieve the symptoms of the disease. Forexample, administration may be by oral, transdermal, parenterial,subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal,or buccal routes.

The compounds of the invention may be used alone, or in combination withother of the known vasodilator drugs.

The compounds of the invention may be formulated into an ointmentcontaining about 0.10 to 10% of the active ingredient in a suitable baseof, for example, white petrolatum, mineral oil and petrolatum andlanolin alcohol. Other suitable bases will be readily apparent to thoseskilled in the art.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional dissolving or suspending the compounds, which are alleither water soluble or suspendable. For administration in the treatmentof the other mentioned pathophysiological disorders. The pharmaceuticalpreparations which can be used orally include push-fit capsules made ofgelatin, as well as soft, sealed capsules make of gelatin and aplasticizer such as glycerol or sorbitol. The push-fit capsules cancontain the active compounds in liquid form that may be mixed withfillers such as lactose, binders such as starches, and/or lubricantssuch as talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as in buffered salt solution. In addition,stabilizers may be added.

In addition to being provided in a liquid form, for example in gelatincapsule or other suitable vehicle, the pharmaceutical preparations maycontain suitable excipients to facilitate the processing of the activecompounds into preparations that can be used pharmaceutically. Thus,pharmaceutical preparations for oral use can be obtained by adhering thesolution of the active compounds to a solid support, optionally grindingthe resulting mixture and processing the mixture of granules, afteradding suitable auxiliaries, if desired or necessary, to obtain tabletsor dragee cores.

Suitable excipients are, in particular, fillers such as sugars, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as inders such as starch, paste using forexample, maize starch, wheat starch, rich starchy, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, crosslinked polyvinyl pyrrolidone, agar,or algenic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which if desired, are resistant togastric juices. For this purpose, concentrated sugar solutions may beused, which may optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tables or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Suitable formulations for intravenous or parenteral administrationinclude aqueous solutions of the active compounds. In addition,suspensions of the active compounds as oily injection suspensions may beadministered. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension include, for example, sodiumcarboxymethyl cellulose, soribitol, and/or dextran. Optionally, thesuspension may also contain stabilizers.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. For example, the presentinvention contemplates certain prodrugs and derivatives of the abovedisclosed compounds, wherein

These compounds may be made by methods known in the art, i.e. theacetylation of the 1-hydroxy or 1-amino or 1-amido derivatives, etc.,disclosed above, with the appropriate acid chloride or acid anhydride.

R⁶ may be

well, when said 1-hydroxy, or 1-amino or 1-amido derivatives are reactedwith the appropriate ortho ester. Similarly, different pharmaceuticalcompositions may be prepared and used with substantially the sameresult. Thus, however detailed the foregoing may appear in text, itshould not be construed as limiting the overall scope hereof; rather,the ambit of the present invention is to be governed only by the lawfulconstruction of the appended claims.

What is claimed is:
 1. A compound useful for treating ocularhypertension represented by formula I:

wherein wavy line attachments indicate either the alpha (α) or beta (β)configuration; dashed bonds represent a double bond or a single bond, Ris a heteroaryl or a substituted heteroaryl radical, R¹ is hydroxyl orhydrocarbyloxy or hetero atom substituted hydrocarbyloxy comprising upto 20 carbon atoms, X is selected from the group consisting of —OR⁶ and—N(R⁶)₂ wherein R⁶ is selected from the group consisting of hydrogen, alower alkyl radical having from 1 to 6 carbon atoms,

or

wherein R⁵ is a lower alkyl radical having from 1 to 6 carbon atoms andY is ═O or represents 2 hydrogen radicals and further provided at leastone of R¹ is a hydrocarbyloxy or an heteroatom substitutedhydrocarbyloxy or a pharmaceutically-acceptable salt thereof.
 2. Thecompound of claim 1 wherein said compound is represented by formula

wherein the hatched segments represent α bonds and the solid trianglerepresents a β bond.
 3. The compound of claim 2 wherein the substituenton the heteroaryl radical is selected from the group consisting of loweralkyl, halogen, trifluoromethyl (CF₃), COR₇, COCF₃, SO₂NR₆, SO₂NH₂, NO₂and CN, wherein R₇ is a lower alkyl radical.